ABSTRACT RCC is the most common type of kidney cancer in adults. RCC is highly resistant to both chemotherapy and radiotherapy; and therapeutic benefits with immunotherapeutic strategies are not remarkable. Aberrant signaling through RTKs plays a major role in renal tumor growth. In both clear cell and papillary RCC, the RTK c-Met is hyperactive. A small molecule c-Met inhibitor (Cabozantinib/XL184) has recently been approved by the FDA for the treatment of advanced RCC. Importantly, acquired drug resistance to c-Met inhibition through gene mutations and chromosome amplification, and dose-dependent toxicity are major hurdles in the clinical use of XL184; and can potentially subdue the anti-tumor effects of c-Met inhibitor therapy. Reports also suggest that c-Met hyperactivation can promote cancer cell migration and immune evasion through the expression of immunoregulatory molecules, leading to metastatic growth of tumor and can potentially subdue the anti-tumor effects of c-Met inhibitor therapy. Therefore, targeting c-Met along with its potent downstream effector molecule(s) can overcome the aforementioned hurdles. One such potential target with immunomodulatory properties is CD73, the ectonucleotidase responsible for the generation of adenosine from extracellular ATP, released from cells due to various stimuli such as hypoxia and metabolic stress. Adenosine-mediated signaling promotes anti-inflammatory responses, which results in immunosuppression. Recent reports point that CD73 is markedly increased in tumor tissues; and it also regulates tumor angiogenesis. Notably, in a pre-clinical tumor model, anti-CD73 treatment enhanced the anti-tumor effects of anti-PD-1 and anti-CTLA-4 antibodies, suggesting that CD73 plays a critical role in inhibiting host anti-tumor immune responses. The cytoprotective role of CD73 in renal tissues during tissue injury and hypoxia is well investigated; yet, the role of CD73 in renal tumor growth has not been studied. In our preliminary studies, we have found that CD73 is overexpressed in renal cancer cells and HGF treatment markedly increased the expression of CD73; and inhibition of c-Met (using XL184) decreased the level of CD73 expression in these cells. Reports suggest a significant cross-talk between c-Met and mTOR signaling axis. Interestingly, we have also observed that the treatment with mTOR inhibitor decreased the expression of CD73 in renal cancer cells; implying that CD73 expression is possibly regulated through mTOR sensitive signaling mechanism(s). However, in-depth molecular analysis of c-Met-mTOR axis in the regulation of CD73 expression needs to be performed; and it is completely unexplored if targeting CD73 can increase the efficacy of c-Met inhibitor in restricting renal tumor growth in vivo. The goal of this project is to explore the role of CD73 in renal tumor growth and to evaluate the therapeutic benefit of targeting both c-Met and CD73 in the treatment of RCC.